The etiology of colorectal cancer and polyps involves genetic as well as environmental factors. The colon is exposed to a large number of genotoxic compounds both from exogamous and endogamous sources. Hereditary non-polyposis colorectal cancer illustrates the importance of DNA repair mechanisms in colorectal carcinogenesis. We hypothesize that polymorphisms in common DNA repair enzymes may also affect the risk of colorectal neoplasia. In the first 4 years of this grant, we have measured several polymorphic enzymes a) related to the metabolism of specific carcinogens from diet and tobacco smoke and b) in the folate pathway. Polymorphisms in other enzymes related to alcohol metabolism (also a source of DNA damage) and rotate metabolism linked to DNA repair via the provision of nucleotides) may also modulate risk. The goals of this competing renewal are to investigate the risk of colon cancer, colorectal adenoma, and colorectal hyperplastic polyps associated with 1) polymorphisms in DNA repair enzymes, specifically in hMLHI, hMSH2, MSH6, hOGGI, XRCC1, XRCC3, XPD, and AGT; 2) polymorphisms related to alcohol metabolism, specifically alcohol dehydrogenases 2,3, and 4; and 3) polymorphisms in enzymes in folate metabolism, specifically in MTHFR, thymidylate synthase (TS), and methionine synthase. We further plan to investigate possible interactions in determining risk of colorectal neoplasia: 1) between relevant environmental exposures and genetic polymorphisms (e.g., dietary intakes of folate and TS polymorphisms; cooked meat and nucleotide-excision repair enzymes); and 2) between polymorphisms in DNA repair genes and those in folate, or alcohol-related enzymes. Two large completed case-control studies of colorectal polyps (adenoma n=550 cases, n=700 controls, and hyperplastic polyps, n=200 cases) and colon cancer (n=1650 cases, n=1950 controls) - with extensive data on diet, alcohol intake, smoking history, and family history, as well as genotype information on other relevant genes - will provide the basis for this study. Information on a number of DNA damage-repair pathway polymorphisms and their interactions with relevant exposures will help build our understanding of the molecular mechanisms involved in the stages of colorectal neoplasia; ultimately, the findings should provide directions for future screening and prevention strategies.